Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The eukaryotic initiation factor 4E (eIF4E) binding protein (4E-BP1) interacts directly with eIF4E and prevents it from forming initiation factor (eIF4F) complexes required for the initiation of cap-dependent mRNA translation. Insulin and other agents induce the phosphorylation of 4E-BP1 at multiple sites, resulting in its release from eIF4E, and this involves signalling through the mammalian target of rapamycin (mTOR). Here we show that D-glucose promotes the ability of insulin to bring about the phosphorylation of 4E-BP1 and the formation of eIF4F complexes. This appears to involve facilitation of the phosphorylation of at least three phosphorylation sites on 4E-BP1, i.e. Thr-36, Thr-45 and Thr-69. Non-metabolizable glucose analogues cannot substitute for D-glucose, but other hexoses can. This suggests that a product of hexose metabolism mediates the permissive effect of glucose. The effect of glucose was concentration-dependent within the range 1-5 mM. In contrast with the situation for 4E-BP1, glucose does not allow full activation of the 70 kDa ribosomal protein S6 kinase (p70 S6k; another target of mTOR signalling) or phosphorylation, in vivo, of its substrate, ribosomal protein S6. Taken together with earlier data showing that amino acids regulate 4E-BP1 and p70 S6k, the present findings show that 4E-BP1 in particular is regulated in response to the availability of both amino acids and sugars.
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PMID:Glucose exerts a permissive effect on the regulation of the initiation factor 4E binding protein 4E-BP1. 1151 50

In freshly isolated rat adipocytes, leucine or its analog norleucine activates the mammalian target of rapamycin (mTOR)-signaling pathway. This results in phosphorylation of the ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), two proteins involved in the initiation phase of protein synthesis. The purpose of the studies reported herein was to address the question of whether or not these in vitro effects of leucine and norleucine on adipocytes could be extended to the intact animal and to other tissues. To accomplish this, food-deprived (18 h) male Sprague-Dawley rats were orally administered solutions (2.5 ml/100 g body wt) containing normal saline (0.9% NaCl), a carbohydrate mixture (26.2% D-glucose and 26.2% sucrose), leucine (5.4%), or norleucine (5.4%). The protein synthetic responses of adipose tissue were measured and compared with those of other tissues. In addition, S6K1 and 4E-BP1 phosphorylation was measured, as was the plasma concentration of insulin and tissue ATP concentrations. Leucine administration stimulated protein synthesis in adipose tissue, gastrocnemius, and kidney but not in liver and heart. Norleucine stimulated protein synthesis in all of the tissues tested but, in contrast to leucine, without affecting plasma insulin concentrations. The carbohydrate meal had no effect on protein synthesis in any tissue tested but elicited a robust increase in plasma insulin. These findings provide support for a role of leucine as a direct-acting nutrient signal for stimulation of protein synthesis in adipose tissue as well as other select tissues. In adipose tissue, the effects of the different treatment conditions on the acute regulation of protein synthesis closely correlated with changes in phosphorylation of S6K1 and 4E-BP1; however, this correlation did not exist in all tissues examined. This result implies that leucine or norleucine may acutely stimulate protein synthesis, at least in some tissues, by a mechanism that is independent of both S6K1 and 4E-BP1 phosphorylation.
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PMID:Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. 1216 44

The effects of rapamycin on glycogen autophagy in the newborn rat liver were studied using biochemical determinations, electron microscopy, and morphometric analysis. Rapamycin increased the fractional volume of hepatocytic autophagic vacuoles, the liver lysosomal glycogen-hydrolyzing activity of acid glucosidase, the degradation of glycogen inside the autophagic vacuoles, and decreased the activity of acid mannose 6-phosphatase. These findings suggest that rapamycin, a known inhibitor of the mammalian target of rapamycin (mTOR) signaling, induces glycogen autophagy in the newborn rat hepatocytes. mTOR may participate in the regulation of this process.
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PMID:Electron microscopic and biochemical study of the effects of rapamycin on glycogen autophagy in the newborn rat liver. 1498 19

Glycogen autophagy, the sequestration and degradation of cell glycogen in the autophagic vacuoles, is a selective, hormonally controlled and highly regulated process, representing a mechanism of glucose homeostasis under conditions of demand for the production of this sugar. In the newborn animals, this process is induced by glucagon secreted during the postnatal hypoglycemia and inhibited by insulin and parenteral glucose, which abolishes glucagon secretion. Hormonal action is mediated by the cAMP/protein kinase A (induction) and phosphoinositides/mTOR (inhibition) pathways that converge on common targets, such as the protein phosphatase 2A to regulate autophgosomal glycogen-hydrolyzing acid glucosidase and glycogen autophagy. Intralysosomal phosphate exchange reactions, which are affected by changes in the calcium levels and acid mannose 6- and acid glucose 6-phosphatase activities, can modify the intralysosomal composition in phosphorylated and nonphosphorylated glucose and promote the exit of free glucose through the lysosomal membrane. Glycogen autophagy-derived nonphosphorylated glucose assists the hyaloplasmic glycogen degradation-derived glucose 6-phosphate to combat postnatal hypoglycemia and participates in other metabolic pathways to secure the fine tuning of glucose homeostasis during the neonatal period.
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PMID:Glycogen autophagy in glucose homeostasis. 1678 26

The enzymes Akt, mTOR, p70(S6K), rpS6, GSK3, and glycogen synthase interact in the control of protein and/or glycogen synthesis in skeletal muscle, and each has been found to respond to exercise and nutrient supplementation. In the present study, we tested the hypothesis that nutrient supplementation post exercise, in the form of a carbohydrate-protein (CHO-PRO) supplement, would alter the phosphorylation state of these enzymes in a manner that should increase muscle protein and glycogen synthesis above that produced by exercise alone. After a 45 min cycling session followed by sprints and again 15 min later, the subjects (n = 8) ingested 400 ml of a CHO-PRO drink (7.8% dextrose and 1.8% protein-electrolyte) or a placebo drink, as assigned using a randomized, counter-balanced design with repeated measures. Biopsies of the vastus lateralis were taken before exercise and at 45 min of recovery. At 45 min after supplementation, CHO-PRO treatment yielded greater phosphorylation of Akt (65%), mTOR (86%), rpS6 (85-fold), and GSK3alpha/beta (57%) than pre-exercise levels (p < 0.05). Although p70(S6k) showed an exercise response after 45 min, there were no differences between treatments. Glycogen synthase (GS) phosphorylation was significantly reduced 45 min after exercise for both treatments, but the reduction in phosphorylation was greatest during the CHO-PRO treatment (3-fold decrease; p < 0.05), indicating greater activation of GS following supplementation. No difference between treatments was detected prior to exercise for any of the enzymes. These results suggest that a post exercise CHO-PRO supplement alters the phosporylation levels of the enzymes tested in a manner that should accelerate muscle glycogen synthesis and protein initiation during recovery from cycling exercise.
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PMID:Post exercise carbohydrate-protein supplementation: phosphorylation of muscle proteins involved in glycogen synthesis and protein translation. 1816 80

Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1alpha) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1alpha translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1alpha down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1alpha. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.
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PMID:Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines. 1856 21

This study aimed to test whether [(18)F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg(-1) per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses >or=5 mg kg(-1) per day (tumour volume treated vs control (T/C): 51% for 5 mg kg(-1) per day and 57% for 15 mg kg(-1) per day). Correspondingly, doses >or=5 mg kg(-1) per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg(-1) per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg(-1) per day and 52% for 15 mg kg(-1) per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.
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PMID:FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo. 1943 99

Globular adiponectin (gAd) induces the generation of reactive oxygen species (ROS) and nitric oxide (NO) in the murine macrophage cell line RAW 264. This study investigated the role of the mammalian target of rapamycin (mTOR) in gAd-induced ROS and NO generation. gAd stimulation induced phosphorylation of mTOR, which peaked at 20 min and dissolved rapidly. Inhibition of phosphatidylinositol 3-kinase activity with wortmannin suppressed gAd-induced phosphorylation of Akt and mTOR. Administration of rapamycin partially reduced gAd-induced generation of intracellular and mitochondrial ROS, but not release of NO. To further confirm the role of mTOR in gAd stimulation, the effect of the activators of AMP-activated protein kinase (AMPK) on gAd-induced mTOR phosphorylation was examined. Pre-treatment with three kinds of AMPK activators, AICAR, 2-deoxy-D-glucose and A-769662, suppressed gAd-induced mTOR phosphorylation. Furthermore, these AMPK activators significantly reduced gAd-evoked intracellular and mitochondrial ROS generation and NO release.
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PMID:Involvement of mTOR in globular adiponectin-induced generation of reactive oxygen species. 1988 50

Leucine has profound effects on glucose metabolism in muscle; however, the effects of leucine on glucose transport in muscle have not been well documented. We investigated the effects of leucine on contraction- and insulin-stimulated glucose transport in isolated rat epitrochlearis muscle in vitro. In the absence of insulin, tetanic contraction increased 3-O-methyl-D-glucose (3-MG) transport and Thr(172) phosphorylation of the catalytic alpha-subunit of 5'-AMP-activated protein kinase (AMPK), a signaling intermediary leading to insulin-independent glucose transport. Leucine (2 mM, 30 min) significantly enhanced contraction-stimulated 3-MG transport and AMPK phosphorylation, accompanied by increased phosphorylation of p70 S6 kinase (p70S6K) Thr(389). The stimulatory effects of leucine on 3-MG transport and AMPK phosphorylation were canceled by STO-609 blockade of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK) or rapamycin blockade of p70S6K. On the other hand, leucine blunted insulin-stimulated 3-MG transport and reduced insulin-stimulated Akt Thr(473) phosphorylation. Leucine increased insulin-stimulated p70S6K Thr(389) phosphorylation and enhanced the inhibitory phosphorylation of the insulin receptor substrate 1 (IRS1) Ser(636/639). Furthermore, the effects of leucine on insulin-stimulated 3-MG transport and IRS phosphorylation were abolished by rapamycin. These results indicate that leucine activates contraction-stimulated glucose transport and inhibits insulin-stimulated glucose transport in skeletal muscle by activating mammalian target of rapamycin (mTOR)/p70S6K signaling. Enhanced increases in contraction-stimulated AMPK Thr(172) phosphorylation and insulin-stimulated IRS1 Ser(636/639) phosphorylation might be responsible for these opposing effects of leucine, respectively.
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PMID:Leucine modulates contraction- and insulin-stimulated glucose transport and upstream signaling events in rat skeletal muscle. 1994 Jan

The elucidation of factors that support human mesenchymal stem cells (hMSCs) growth has remained unresolved partly because of the reliance of many researchers on ill-defined, proprietary medium formulation. Thus, we investigated the effects of high glucose (D-glucose, 25 mM) on hMSCs proliferation. High glucose significantly increased [(3)H]-thymidine incorporation and cell-cycle regulatory protein expression levels compared with 5 mM D-glucose or 25 mM L-glucose. In addition, high glucose increased transforming growth factor-beta1 (TGF-beta(1)) mRNA and protein expression levels. High glucose-induced cell-cycle regulatory protein expression levels and [(3)H]-thymidine incorporation, which were inhibited by TGF-beta(1) siRNA transfection and TGF-beta(1) neutralizing antibody treatment. High glucose-induced phosphorylation of protein kinase C (PKC), p44/42 mitogen-activated protein kinases (MAPKs), p38 MAPK, Akt, and mammalian target of rapamycin (mTOR) in a time-dependent manner. Pretreatment of PKC inhibitors (staurosporine, 10(-6) M; bisindolylmaleimide I, 10(-6) M), LY 294002 (PI3 kinase inhibitor, 10(-6) M), Akt inhibitor (10(-5) M), PD 98059 (p44/42 MAPKs inhibitor, 10(-5) M), SB 203580 (p38 MAPK inhibitor, 10(-6) M), and rapamycin (mTOR inhibitor, 10(-8) M) blocked the high glucose-induced cellular proliferation and TGF-beta(1) protein expression. In conclusion, high glucose stimulated hMSCs proliferation through TGF-beta(1) expression via Ca(2+)/PKC/MAPKs as well as PI3K/Akt/mTOR signal pathways.
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PMID:High glucose regulates cyclin D1/E of human mesenchymal stem cells through TGF-beta1 expression via Ca2+/PKC/MAPKs and PI3K/Akt/mTOR signal pathways. 2023 5


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